Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family

Abstract

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPKpathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential

“…Stimulation of dormant cells by growth factors, such as epidermal growth factor (EGF), insulin-like growth factor-I (IGF-1) and platelet-derived growth factor (PDGF), activates the mitogen-activated protein kinase (MAPK) (Erk1/2) cascade and triggers the transition to the proliferating stage [63,64]. One of the important substrates of MAPK is CAD.…”